RAGE: a potential target for Epimedium’s anti-neuroinflammation role in vascular dementia—insights from network pharmacology and molecular simulation

Vascular dementia (VaD), a cognitive impairment resulting from cerebrovascular issues, could be mitigated by Epimedium. This study investigates Epimedium's efficacy in VaD management through a systematic review, network pharmacology, molecular docking, and molecular dynamic simulations (MDS). Comprehensive literature searches were conducted across various databases. Epimedium's pharmacological properties were analyzed using the TCMSP database. Integration with the Aging Atlas database enabled the identification of shared targets between Epimedium and VaD. A protein-protein interaction (PPI) network was constructed, and central targets' topological attributes were analyzed using Cytoscape 3.9.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using “ClusterProfiler” R package. The interactions between Epimedium and central targets were assessed by Molecular docking and MDS. Epimedium and its 23 bioactive components counteracted oxidative stress, neuroinflammation, and neuronal damage, thereby attenuating cognitive deterioration in VaD. A total of 78 common targets were identified, with 22 being significantly related to aging. Enrichment analysis identified 1769 GO terms and 139 KEGG pathways, highlighting the AGE-RAGE signaling pathway. Molecular docking revealed that 23 bioactive components, except Linoleyl acetate, effectively interacted with top central targets (JUN, MAPK14, IL6, FOS, TNF). MDS demonstrated that flavonoids Icariin, Kaempferol, Luteolin, and Quercetin formed stable complexes with RAGE. The study identifies RAGE as a novel therapeutic target for Epimedium in the mitigation of VaD via its anti-inflammatory properties.

血管性痴呆（Vascular dementia, VaD）是一类由脑血管病变引发的认知功能损害，可通过淫羊藿（Epimedium）得到缓解。本研究采用系统综述、网络药理学、分子对接及分子动力学模拟（Molecular Dynamic Simulations, MDS）手段，探究淫羊藿在血管性痴呆管理中的药效作用。研究在多类数据库中开展了全面的文献检索，通过TCMSP数据库分析淫羊藿的药理特性；结合衰老图谱（Aging Atlas）数据库，识别出淫羊藿与血管性痴呆的共有靶点。本研究构建了蛋白质-蛋白质相互作用（Protein-Protein Interaction, PPI）网络，并使用Cytoscape 3.9.1软件对核心靶点的拓扑属性进行分析；采用"ClusterProfiler"R包完成基因本体（Gene Ontology, GO）及京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析；通过分子对接与分子动力学模拟，评估淫羊藿与核心靶点间的相互作用。淫羊藿及其23种生物活性成分可对抗氧化应激、神经炎症与神经元损伤，进而减轻血管性痴呆的认知功能衰退。本研究共识别出78个共有靶点，其中22个与衰老显著相关；富集分析得到1769个GO条目与139条KEGG通路，核心通路为AGE-RAGE信号通路。分子对接结果显示，除乙酸亚油酯（Linoleyl acetate）外，其余23种生物活性成分均可与核心靶点（JUN、MAPK14、IL6、FOS、TNF）有效结合；分子动力学模拟结果表明，黄酮类化合物淫羊藿苷（Icariin）、山奈酚（Kaempferol）、木犀草素（Luteolin）及槲皮素（Quercetin）可与晚期糖基化终末产物受体（RAGE）形成稳定复合物。本研究证实RAGE可作为淫羊藿通过抗炎作用缓解血管性痴呆的新型治疗靶点。